Abstract: The activation of the immune response to yield durable antitumor immunity and anti-cancer activity has become a reality. However, an unmet medical need exists in that not all cancer patients respond to anti-PD1 or other checkpoint inhibitors currently in clinical use. This has led to a push to identify other negative regulators of the innate and adaptive immune response for anti-cancer therapeutics. Myeloid cells including macrophages and myeloid derived suppressor cells, play important roles in mediating tumor growth and immunosuppression. The long-term goal is to better understand the signaling mechanisms in myeloid cells which mediate tumor immunosuppression and anti-tumor immunity observed in the tumor microenvironment (TME). The objective in this particular application is to determine the role of myeloid Syk kinase in mediating macrophage mediated immunosuppression and to test Syk or novel dual Syk/PI3K inhibitors in combination with ?PD1 mAb for maximal adaptive immune response against the tumor. The central hypothesis motivating this research is that Syk kinase programs M?s to immunosuppressive phenotype in the TME and its inhibition along with PI3K and/or a check point inhibitors will activate anti-tumor immune responses. This hypothesis has been formulated on the basis of genetic evidence generated in our laboratory utilizing PI3K? -/- and Syk-/- murine models for immuno-oncology. The rationale for the proposed research is that understanding molecular mechanisms by which myeloid Syk promote immunosuppression has the potential to translate Syk and dual Syk/ PI3K inhibitors to treat cancers driven by the M?-dependent immunosuppressive TME. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: Aim 1, we will determine the role of Syk kinase in tumor growth and immunosuppression. Aim 2 we will determine the mechanism by which the Syk kinase regulates immunosuppressive transcriptional programming in macrophages including changes in the M? transcriptome. Aim 3 we will determine the effect of either Syk inhibitor or dual Syk/PI3K inhibitor in combination with immunotherapy modulators to augment anti-tumor immune response. The approach is innovative because it utilizes a novel small-molecule inhibitory chemotype, SRX3207 which hits both targets, Syk and PI3K in kinase and cell based assays and that both inhibition activate antitumor immunity. The significance of our proposal lies in our capacity to provide an optimizable promising single anticancer agent which will potently activate the immune response via multiple orthogonal mechanisms and result in a durable antitumor immune response. The candidate is firmly committed to a career in cancer research and is strongly supported by the institution for her pathway to independence. She is an Assistant Project Scientist in Division of Pediatrics at University of California, San Diego. The outlined proposal builds on the candidate?s previous research experience in the field of myeloid cell signaling and a career development plan that includes focused coursework, and collaborations from a multi-disciplinary group of established researchers that will help to complete the proposed studies.